Molecular mechanisms in proximal tubular and small intestinal phosphate reabsorption (Plenary Lecture)

Citation
H. Murer et al., Molecular mechanisms in proximal tubular and small intestinal phosphate reabsorption (Plenary Lecture), MOL MEMBR B, 18(1), 2001, pp. 3-11
Citations number
83
Categorie Soggetti
Cell & Developmental Biology
Journal title
MOLECULAR MEMBRANE BIOLOGY
ISSN journal
09687688 → ACNP
Volume
18
Issue
1
Year of publication
2001
Pages
3 - 11
Database
ISI
SICI code
0968-7688(200101/05)18:1<3:MMIPTA>2.0.ZU;2-V
Abstract
Renal and small intestinal (re-) absorption contribute to overall phosphate ( P-i)- homeostasis. In both epithelia, apical sodium (Na+)/P-i-cotransport across the luminal (brush border) membrane is rate limiting and the target for physiological/pathophysiological alterations. Three different Na/P-i-c otransporters have been identified: (i) type I cotransporter(s)-present in the proximal tubule-also show anion channel function and may play a role in secretion of organic anions; in the brain, it may serve vesicular glutamat e uptake functions; (ii) type II cotransporter(s) seem to serve rather spec ific epithelial functions; in the renal proximal tubule (type IIa) and in t he small intestine (type IIb), isoform determines Na+-dependent transcellul ar P-i-movements; (iii) type III cotransporters are expressed in many diffe rent cells/tissues where they could serve housekeeping functions. In the sm all intestine, alterations in P-i-absorption and, thus, apical expression o f IIb protein are mostly in response to longer term (days) situations (alte red P-i-intake, levels of 1.25 (OH2) vitamin D-3, growth, etc), whereas in renal proximal tubule, in addition, hormonal effects (e.g. Parathyroid Horm one, PTH) acutely control (minutes/hours) the expression of the IIa cotrans porter. The type II Na/P-i-cotransporters operate (as functional monomers) in a 3 Na+:1 P-i stoichiometry, including transfer of negatively charged (- 1) empty carriers and electroneutral transfers of partially loaded carriers (1 Na+, slippage) and of the fully loaded carriers (3 Na+, 1 P-i). By a ch imera (IIa/IIb) approach, and by site-directed mutagenesis (including cyste ine-scanning), specific sequences have been identified contributing to eith er apical expression, PTH-induced membrane retrieval, Na+-interaction or sp ecific pH-dependence of the IIa and IIb cotransporters. For the COOH-termin al tail of the IIa Na/P-i-cotransporter, several interacting PDZ-domain pro teins have been identified which may contribute to either its apical expres sion (NaPi-Cap1) or to its subapical/lysosomal traffic (NaPi-Cap2).